Natural products reflect good biological activities in many ways, particularly in the treatment of cancers, inflammation, cardiovascular disease and immune disease. Cantharidin (see Formula (a)) is a natural anti-tumor drug obtained from the dried body of the Chinese blister beetles. Its clinical application is limited due to severe side-effects and highly toxicity. Norcantharidin (see Formula (b)), a derivative of cantharidin, can reduce the side-effect in the urinary system to some extent and increase the number of white blood cells with comparable anti-cancer activity. Both of them have been used as an anticancer agent in clinical application, by inducing apoptosis in many types of tumor cells, such as hepatoma, breast, oesophageal, colorectal and lung carcinoma, etc. Based on these natural products, a lot of small molecule drugs were synthesized to expand the clinical application. Our target is to explore better analogues of norcantharidin with better anti-cancer activity and less side-effects.

Our group mainly aimed at the asymmetric reactions of norbornadiene derivatives with terminal alkynes. Recently, it was reported in Fan, B. M., et al. (Ligand-controlled enantioselective [2+2] cycloaddition of oxabicyclic alkenes with terminal alkynes using chiral iridium catalysts. Org Lett, 2010. 12(2): p. 304-6, and Hu, J., et al., A study on the substituent effects of norbornadiene derivatives in iridium-catalyzed asymmetric [2+2] cycloaddition reactions. Org Biomol Chem, 2013. 11(14): p. 2294-301) that mixture of iridium and chiral xylyl-phanephos is an efficient catalyst for the [2+2] cycloadditions of norbonadiene derivatives and terminal alkynes (up to 99% ee). Interestingly, when the diphosphine ligand by simply changing from planar chiral to axial chiral (e.g. SYNPHOS), hydroalkynylation products were generated instead by direct addition the C—H bond of terminal alkynes to the C═C bond of norbornadienes derivatives. Fan et al. also found that the hydroalkynylation products of 7-oxabenzonorbornadienes derivatives have shown good anti-cancer activities (U.S. patent application Ser. No. 13/729,479).
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